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Biomedical subjects

M J Peach

Publications and source records attributed to M J Peach.

At least 163 records · Page 9Linked to original sources
PubMed1976

Changes in cardiovascular and adrenal cortical responses to angiotensin III induced by sodium deprivation in the rat.

The restriction of dietary sodium intake is known to depress the cardiovascular responses to angiotensin II and increase the sensitivity of the adrenal zona glomerulosa to this steroidogenic octapeptide. In sodium-repleted animals, angiotensin III is a weak pressor substance and a potent stimulant of aldosterone biosynthesis. The effect of a low sodium diet on vascular and steroidogenic responses to angiotensin II and angiotensin III was investigated. In nephrectomized rats, angiotensin III had one-third of the pressor activity relative to angiotensin II when either normal or sodium-deprived animals were compared. When administered subcutaneously (sc) to rats, angiotensin II and III induced comparable steroidogenic responses, whereas only angiotensin II significantly elevated blood pressure. The comparison of cell suspensions from control adrenals with suspensions of adrenals from sodium-deprived animals showed that the zona glomerulosa from rats on low sodium diets had increased wet weight (20%), cell protein (25%), and basal steroidogenic rats (45%). Adrenocorticotropic hormone (ACTH)-induced responses in adrenal cells from low sodium animals were about twice the responses of cells from normal adrenals. Angiotensin II and III stimulated the cortex at a threshold concentration of 5 X 10(-10) M and induced a maximum response at about 5 X 10(-8) M in cells prepared from normal rat adrenals. In cells dispersed from adrenal capsules of sodium-deprived rats, the maximal steroidogenic response to angiotensin II occurred at 3 X 10(-8) M, whereas angiotensin III was maximal at 1 X 10(-9) M. Aldosterone synthesis induced by both peptides was increased approximately 45% in adrenal cells from low salt rats. At 0.9 mumol/kg, sc, Sar-1, Ile-8-angiotensin II antagonized cardiovascular responses to angiotensin II and did not alter aldosterone in the sodium-deprived rat. In contrast, treatment with Ile-7-angiotensin III blocked the adrenal cortex but not the vascular actions of angiotensin II. These data are consistent with a role for angiotensin III in the renin-angiotensin-aldosterone response to sodium deprivation.

Adrenal Cortex↗
PubMed1976

Mechanism for the postive inotropic effect of angiotensin II on isolated cardiac muscle.

Angiotensin II (A II) and analogues were tested for their ability to restore electrical and mechanical activity to cardiac muscle preparations in which the fast Na+ channels had been inactivated by partial depolarization (22-27 mM K+) or by tetrodotoxin (TTX). The partially depolarized or TTX-blocked preparations were chosen because under these conditions electrical and mechanical responses are primarily Ca2+ -dependent. In depolarized rabbit right atria, A II restored spontaneous mechanical and electrical activity (measured by both intracellular and extracellular recording techniques). The frequency of action potential discharge was concentration-dependent; the threshold concentration of A II was 10(-10) M, the ED50 was 8 X 10(-9) M, and the maximum effect was observed at 5 X 10(-8) M. In contrast, depolarized guinea pig atria were insensitive to A II, Sar1-angiotensin II, and des-Asp1-angiotensin II, even at concentrations as high as 10(-5) M. Rabbit papillary muscle (TTX-blocked), embryonic (18-day) chick heart (partially depolarized) and chick heart reaggregates (TTX-blocked) responded similarly to rabbit atria in that A II (9.6 X 10(-7) M) restored both electrical and mechanical activity. We found that in these preparations the action of A II was unaffected by propranolol (5.0 X 10(-6) M to 5.0 X 10(-5) M) but was blocked by Mn2+ (10(-3) M), D-600 (1 X 10(-7) g/ml) and the specific A II antagonists Sar1-Ala8-angiotensin II (P-113) (5.0 X 10(-5) M) and Sar1-Ile8-angiotensin II (5.28 X 10(-5) M). We conclude that the positive inotropic effect of A II on the myocardium is due to its ability to increase transmembrane ion movements in or through the cell membrane. The ability of Mn2+ and D-600 to block this effect suggests that this ion movement is via the so-called "slow channels."

Action Potentials↗
PubMed1976

Role of converting enzyme in the cardiovascular and adrenal cortical responses to (des-Asp1)-angiotensin I.

(Des-Asp1)-angiotensin I, angiotensin II and III were evaluated for pressor activities in conscious nephrectomized rats and for steroidogenic actions in rat adrenal zona glomerulosa. The pressor effect of this angiotensin nonapeptide was similar to that found with mole-equivalent doses of angiotensin III (one-third as active as angiotensin II) and was significantly attenuated by pretreatment with the 0. jararaca nonapeptide converting enzyme inhibitor. Hence, (des-Asp1)-angiotensin I is a substrate for converting enzyme in vivo, and the rapid conversion indicates that an alternate pathway for the formation of angiotensin III could exist. (Des-Asp1)-angiotensin I possessed only 0.1% of the activity of angiotensin III as a steroidogenic agent in cell suspensions of rat adrenal zona glomerulosa. Angiotensin I was a weak steroidogenic agent in vitro (1%) and was not blocked by an inhibitor of converting enzyme. Adrenal cells dispersed from the outer zone of the cortex would appear to be devoid of significant converting enzyme activity.

Adrenal Glands↗
PubMed1976

Angiotensin antagonists and the adrenal cortex and medulla.

Several analogs of angiotensin in which the phenylalanine in position 8 of the peptide chain was replaced by an aliphatic amino acid residue are specific antagonists of angiotensin in aorta, the adrenal medulla, and adrenal zona glomerulosa. In the adrenal cortex and medulla, all actapeptide analogs have more agonist activity than in aortic strips. In studies with N-terminally substituted analogs, it appears that adrenal degradation of the angiotensin molecule by aminopeptidase(s) does not occur or is not retarded by N-terminal mocifications such as sarcosine substitution. The decapeptide analog [Ile8]-angiotensin I and heptapeptide analog [des-Asp1, Ile8]-angiotensin II were excellent antagonists in the adrenal medulla and each peptide was devoid of intrinsic activity. These substituted homologs of angiotensin may offer a novel approach for the development of selective antagonists of angiotensin receptors. In the adrenal cotex, [des-Asp1, Ile8]-heptapeptide possessed greater receptor affinity than any of the angiotensin octapeptides studied. This C-terminally substituted heptapeptide does have significant intrinsic activity in the adrenal cortex which would limit the use of this compound as an antagonist of vascular responses to angiotensin II. In studies with [Ile8]-angiotensin II, [Sar1, Ile8]-angiotensin II, and [des-Asp1, Ile8]-angiotensin II, the pA2 values calculated indicate that the N-terminal residue is not important for receptor binding in the adrenal cortex but may be of significance in binding to adrenal medullary and aortic smooth muscle receptors. At the present time it appears unlikely that any single animal model or assay system can reliably predict the agoinst/antagonist activities of angiotensin analogs for all the various end organs which respond to the angiotensins.

Adrenal Cortex↗
PubMed1975

Inhibition of catecholamine release by tolbutamide and other sulfonylureas.

Tolbutamide and other sulfonylureas inhibited spontaneous and nicotine-induced release of catecholamines from the perfused cat adrenal gland and nicotine-induced release of [3-H]norepinephrine from isolated guinea pig hearts. Of the sulfonylureas tested, the order to potency of this inhibitory effect paralled the hypoglycemic action. These results raise the possibility that the inhibition of the sympathoadrenal system may contribute in part to the hypoglycemic action of sulfonylureas.

Adrenal Glands↗
PubMed1975

Synthesis and evaluation of (Des-Asp1)angiotensin I as a precursor for (Des-Asp1)angiotensin II ("Angiotensin III").

The nonapeptide [des-Asp1]angiotensin I (IV), synthesized by Merrifield's solid-phase procedure, was tested as a possible substrate for the converting enzymes from porcine lung and plasma. IV, [des-Asp1]angiotensin II (III), [des-(Asp1,Arg2)]angiotensin II (V), [des-(Asp1,Arg2,Val3)]angiotensin II (VI), [Sar1,Ile8]angiotensin II (VII), and [des-Asp1,Ile8]angiotensin II (VIII) possessed 0.5, 20, 2, 0 less than 0.1, and less than 0.01% of the inotropic activity (rabbit atria), 1, 15, 5, 0, 3, and 0% secretory activity of the cat adrenal medulla, and 0.0, 150, 0.5, 3, and 10% of the adrenal steroidogenic activity of angiotensin II, respectively. When tested for their antagonistic activity in the above tissues, only VII and VIII were found to inhibit responses to angiotensin II. The pA2 values for VII and VIII were 8.31 and 10.0 in the adrenal cortex and 9.31 and 9.16 in the adrenal medulla, respectively. All these peptides were also tested as product inhibitors for the plasma and lung converting enzymes. With the plasma enzyme, the ID50 values were II, 1.6 X 10(-4) M; III, 5 X 10(-5) M; V, 1.2 X 10(-4) M; VI 5 X 10(-4) M; VII 5 X 10(-5) M; VIII, 5 X 10(-4) M. Thus, IV is a good substrate for converting enzymes from lung and plasma while all other compounds were inhibitors of these enzymes. The most potent inhibitors of converting enzyme were III followed by VII and VIII. With the exception of II and III, all the other analogs had very low intrinsic activities, per se. These results suggest (a) an alternate pathway for the formation of heptapeptide III, viz., by the action of converting enzyme on the nonapeptide IV, and (b) that III may also be acting as inhibitor of the converting enzyme by the feedback mechanism.

Angiotensin II↗
PubMed1975

Angiotensin III: (DES-Aspartic Acid-1)-Angiotensin II. Evidence and speculation for its role as an important agonist in the renin - angiotensin system.

Evidence is reviewed that three and possibly four peptides formed from renin substrate have biological activity that merits their recognition as agonists. The decepeptide angiotensin I affects sites in the central nervous system and adrenal medulla. The octapeptide angiotensin II affects vascular and cardiac sites that mediate acute pressor responses, and also causes direct feedback inhibition of renin release. The heptapeptide (des-asp-1)-angiotensin II ("angiotensin III") stimulates aldosterone release.. It may exert its effects intracellularly at the adrenal glomerulosa and other sites. The fourth candidate is the (des-asp-1)-angiotensin I nonapeptide, but nothing is known of its activity or circulating levels. This formulation of the angiotensin reaction sequence and the effects of its individual congeners suggests several experiments. It also permits simple explanations for previously confusing data, such as the inability of immunization and anti-angiotensin II to prevent aldosterone responses, and the paradoxical preservation of adrenal responsiveness in Bartter's syndrome.

Adrenal Cortex↗
PubMed1975

Differentiation of neurogenic and myocardial angiotensin II receptors in isolated rabbit atria.

The effect of angiotensin on the action of tyramine was studied in isolated rabbit left atria paced by point and field stimulation to more clearly define the interaction of angiotensin with the sympathetic nervous system. Administration of angiotensin resulted in similar increases in contractility in both point- and field-stimulated atria. In point-stimulated preparations only the muscle is stimulated to contract, whereas in field-stimulated preparations both nerve and muscle are stimulated. 1-Sar-8-Ala-angiotensin II completely blocked the direct inotropic effect of angiotensin in a molar dose ratio of 3:1 in both point- and field-stimulated preparations. However, angiotensin (0.05-10 ng/ml) potentiated the inotropic effect of tyramine in field-stimulated atria only. This facilitatory effect was not inhibited by 1-Sar-8-Ala-angiotensin II at a molar dose ratio of 3:1; indeed, a ratio of 500:1 was necessary for complete blockade of this angiotensin-induced potentiation. This antagonist in odses of 0.1-1000 ng/ml was without contractile effect in any preparation, regardless of whether tyramine was present. The data suggest the presence of (1) a presynaptic angiotensin receptor that, in the presence of sympathetic nerve stimulation, modulates the release of norepinephrine and (2) a second angiotensin receptor in cardiac tissue that directly influences myocardial contractility.

Angiotensin II↗
PubMed1975

Selective inhibition by des-1-Asp-8-lle-angiotensin ii of the steroidogenic response to restricted sodium intake in the rat.

Angiotensin III (des-1-Asp-angiotensin II) is a potent steriodogenic agent in many species. The effects of the heptapeptide in the adrenal zona glomerulosa are resistant to blockade by C-terminally substituted analogues of angiotensin II (1-Sar-8-Ile- or 1-Sar-8-Ala-octapeptides). For this reason, the effects of 7-Ile-angiotensin III, a C-terminally substituted analogue of the heptapeptide, and 1-Sar-8-Ile-angiotensin II on aldosterone biosynthesis in rabbit adrenal cortical cell suspensions and on urinary aldosterone excretion in sodium-deprived rats were studied. In the vitro studies, 7-Ile-angiotensin III was a better antagonist of angiotensin II- or angiotensin III-induced steroidogenesis than was 1-Sar-8-Ile-angiotensin II. In the rats, subcutaneously administered 1-Sar-8-Ile-angiotensin II (0.9 mumoles/kg) produced prolonged blockade of the pressor responses to exogenous angiotensin II. 70Ile-angiotensin III (0.9 mumoles/kg) had no effect on resting blood pressure or on blood pressure responses to angiotensin II infusions. At the doses studied, however, 7-Ile-angiotensin III caused a marked decrease (50%) in aldosterone excretion in sodium-deprived rats, but 1-Sar-8-Ile-angiotensin II had no effect on aldosterone excretion. In the sodium-deprived rats, the administration of 7-Ile-angiotensin Ile was not associated with an acute increase in plasma renin activity, but treatment with 1-Sar-8-Ile-angiotensin II resulted in a sixfold increase in plasma renin activity, but otensin III was not associated with an acute increase in plasma renin activity, but treatment with 1-Sar-8-Ile-angiotensin II resulted in a sixfold increase in plasma renin activity. These results are consistent with a role for angiotensin III in the control of aldosterone biosynthesis.

Adrenal Cortex↗
PubMed1974

Inhibition of induced aldosterone biosynthesis with a specific antagonist of angiotensin II.

The present study determined the effect of [Sar(1)-Ile(8)]-angiotensin II on steroidogenesis and induced aldosterone synthesis by the octapeptide angiotensin II, the heptapeptide des-Asp(1)-angiotensin II, and adrenocorticotropic hormone. Rabbit adrenal cells were suspended by incubation of the capsular cortical tissue with collagenase, and aldosterone levels were determined by immunoassay. Steroidogenic responses to angiotensin II and des-Asp(1)-angiotensin were essentially the same. [Sar(1)-Ile(8)]-angiotensin II (10(-7) to 5 x 10(-7) M) had no significant effect on basal aldosterone biosynthesis. However, when added with steroidogenic peptides, it completely blocked the effect of angiotensin II and des-Asp(1)-angiotensin II but not of adrenocorticotropic hormone. The dose ratio of the antagonist to angiotensin II that gave 100% inhibition was about 2:1 and to des-Asp(1)-angiotensin II, about 50:1. The data suggest that des-Asp(1)-angiotensin II has a much higher affinity for the angiotensin receptor in adrenal cortex than angiotensin II.

Adrenal Glands↗
PubMed1972

Stimulation of release of adrenal catecholamine by adenosine 3':5'-cyclic monophosphate and theophylline in the absence of extracellular Ca 2+ .

Stimulation of catecholamine release was studied in the isolated adrenal of the cat during retrograde perfusion. Theophylline, adenosine 3':5'-cyclic monophosphate (cyclic AMP), and dibutyryl-cyclic AMP stimulated catecholamine release in adrenal chromaffin tissue; adenosine, 2'-AMP, 3'-AMP, and 5'-AMP were ineffective. Addition of theophylline for 5-15 min had no effect on catecholamine release induced by KCl or nicotine, but it significantly increased the responses to cyclic AMP and its dibutyryl derivative. Glands perfused with Ca(2+)-free Locke's solution for 30-180 min rapidly lost their responsiveness to KCl or nicotine. In contrast, exposure to Ca(2+)-free medium for 180 min had no effect on secretory responses to either the cyclic nucleotides, themselves, or to methylxanthine-induced potentiation of cyclic AMP responses. Thus, dibutyryl-cyclic AMP, cyclic AMP, and theophylline do not require extracellular Ca(2+) to release adrenal catecholamines. They may act by translocating intracellular bound Ca(2+) or by a mechanism independent of calcium.

Adenosine↗